Solvent-free mechanochemical preparation of phosphonium salts, phosphorus ylides, and olefins

ABSTRACT

The present invention provides a method of preparing a phosphonium salt of the formula [R 1 R 2 R 3 P—CR 4 R 5 R 6 ]X, comprising ball-milling a phosphine of the formula R 1 R 2 R 3 P with a compound of the formula XCR 4 R 5 R 6 ; a method of preparing a phosphorus ylide of the formula R 1 R 2 R 3 P═CR 4 R 5 , comprising ball-milling a phosphonium salt of the formula [R 1 R 2 R 3 P—HCR 4 R 5 ]X in the presence of a base; and a method of preparing an olefin of the formula R 4 R 5 C═CR 7 H or R 4 R 5 C═CR 7 R 8 , comprising ball-milling a phosphorus ylide of the formula R 1 R 2 R 3 P═CR 4 R 5  with a compound of the formula R 7 C(O)H or R 7 C(O)R 8 . The inventive method produces phosphonium salts and phosphorus ylides by mechanical processing solid reagents under solvent-free conditions. The advantages of the present invention over conventional solution methods, include: (1) extremely high selectivity; (2) high yields; (3) low processing temperatures; (4) simple and scalable reactions using commercially available equipment; and (5) the complete elimination of solvents from the reaction.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This patent application claims the benefit of U.S. patent applicationSer. No. 60/354,825, which was filed on Feb. 6, 2002.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

This invention was made in part with Government support under ContractNumber W-7405-ENG-82 awarded by the Department of Energy (DOE). TheGovernment may have certain rights in this invention.

FIELD OF THE INVENTION

This invention pertains to the solvent-free mechanochemical preparationsof phosphonium salts and phosphorus ylides, and to utilizing suchphosphorus ylides in carrying out the solvent-free synthesis of desiredunsaturated organic compounds employing the Wittig-Horner reaction (alsoknown as the Wittig reaction).

BACKGROUND OF THE INVENTION

Phosphonium salts are used as agricultural chemicals, phase transfercatalysts, physiologically active compounds, corrosion inhibitors, flameretardants, anti-static and softening agents (see, e.g., WO 99/28287; JP2000-265085; EP 139260; U.S. Pat. Nos. 4,246,031; and 4,943,380).However, the current major application of phosphonium salts isconsidered to be their transformation into phosphorus ylides, whichphosphorus ylides further participate in the Wittig-Horner reactionleading to diverse unsaturated organic compounds (W. A. Johnson, Ylidesand imines of phosphorus. John Wiley & Sons, Inc. New York, 1993).

Typically, phosphonium salts are synthesized in solution by a broadvariety of methods, which include reactions of phosphines with alcoholsor oxiranes, with aromatic organic halides in the presence of metalsalts, or with diazo compounds (P. Beck in Organic Phosphorus Compoundsvol. 2, Eds.: G. M. Kosolapoff, L. Maier, John Wiley & Sons, Inc. NewYork, p. 189, 1972; DE 19914193; K. Sasse in Methoden der OrganischenChemie (Houben-Weil), Bd XII/1, Ed.: E. Müller, Georg Thieme Verlag,Stuttgart, p. 79, 1963; K. Jödden in Methoden der Organischen Chemie(Houben-Weil), Bd E1, Ed.: M. Regitz, Georg Thieme Verlag, Stuttgart,New York, p. 491, 1982). A conventional method of preparingalkyl-substituted phosphonium salts is the reaction of ternaryphosphines with alkyl halides in appropriate organic solvents.Alternatively, liquid organic halides can be used as the reaction media.Although successful in many instances, the preparation of phosphoniumsalts from phosphines and alkyl halides using these methods can becomplicated by side reactions, thus lowering the overall yield of thedesired compounds. In particular, reactions of ternary phosphines withα-bromoketones are unreliable because alkylation of phosphines isaccompanied by the formation of O-phosphorylated products and by thedehydrobromination of the starting bromoketones (W. A. Johnson, Ylidesand imines of phosphorus. John Wiley & Sons, Inc. New York, 1993;Borowitz et al., J. Org. Chem. 34, 1595 (1969)).

In the presence of a base, phosphonium salts can form phosphorus ylides.Phosphorus ylides find use in the synthesis of vitamins, terpenoids,steroids, hormones, prostaglandins, amino acids, nucleotides,physiologically active compounds, and transition metal complexes, and inpolymerization processes. However, as previously noted, it is believedthat the major use of phosphorus ylides is their reaction with diverseorganic carbonyl derivatives in the Wittig-Homer reaction, which allowsfor the preparation of various unsaturated organic substances.Conventionally and exclusively, the generation of phosphorus ylides isperformed in a solution using a wide variety of solvents (see, e.g., W.A. Johnson, Ylides and imines of phosphorus. John Wiley & Sons, Inc. NewYork, 1993; WO 99/28287; Hudson in The Chemistry of OrganophosphorusCompounds vol. 1, Ed.: F. R. Hartley, John Wiley & Sons, Ltd. New York,p. 386, 1990; The Chemistry of Organophosphorus Compounds, vol. 3:Phosphonium Salts, Ylides and Phosphoranes. Ed.: F. R. Hartley, JohnWiley & Sons, Ltd. New York, 1994).

Additionally, the bases used in the preparation of such phosphorusylides should possess an appropriate strength, as is known. Examples ofsuitable bases include alkali metal carbonates, alkali metal hydroxides,alkali metal alkoxides, methyl, butyl or phenyllithium. As with thepreparation of phosphonium salts, the generation of phosphorus ylides insolution can be complicated by undesirable side reactions. Consequently,phosphorus ylides must usually be prepared by means of meticulous,multiple-stage processes to avoid the preparation of the correspondingphosphonium salts (Aitken et al., Phosphorus, Sulfur and Silicon 101,281 (1995)). Phosphorus ylides can sometimes react with the reactionsolvent, thereby further complicating the synthesis. As a result, thechoice of the reaction media is critical for both the generation ofphosphorus ylides and in carrying out the Wittig-Horner reaction.

Environmental and health issues are other concerns with the use oforganic solvents in the conventional preparation of phosphonium saltsand phosphorus ylides. The reaction solvents can end up in wastestreams, thereby straining the environment and causing health problemsin the individuals exposed to them. Despite tremendous efforts directedtowards the minimization of both environmental and health impacts ofsolvents, handling and elimination of solvents-related waste stillremains one of the most difficult environmental and health problems. Aneffective approach to minimize the solvent-related chemical pollution isthe replacement of solvents in both the industry and research laboratoryby alternative materials acceptable from both environmental and healthstandpoints. However, a much more desirable method of resolvingecological problems caused by solvent wastes would be one thateliminates the use of solvents required for carrying out the particularchemical reactions altogether.

The present invention provides such a method. These and other advantagesof the invention, as well as additional inventive features, will beapparent from the description of the invention provided herein.

BRIEF SUMMARY OF THE INVENTION

The invention provides a method of preparing a phosphonium salt of theformula [R¹R²R³P—CR⁴R⁵R⁶]X, comprising ball-milling a phosphine of theformula R¹R²R³P with a compound of the formula XCR⁴R⁵R⁶; wherein R¹⁻³are independently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; wherein R⁴⁻⁶ areindependently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; and wherein X is a mono- orpolyvalent anion. The invention further provides a method of preparing aphosphorus ylide of the formula R¹R²R³P═CR⁴R⁵, comprising ball-milling aphosphonium salt of the formula [R¹R²R³P—HCR⁴R⁵]X (i.e., wherein R⁶ isH) in the presence of a base; wherein R¹⁻³ are independently selectedfrom the group consisting of hydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl,aralkyl, and aryl; wherein R⁴ and R⁵ are independently selected from thegroup consisting of hydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl, andaryl; and wherein X is a mono- or polyvalent anion. A third aspect ofthe invention provides a method of preparing an olefin of the formulaR⁴R⁵C═CR⁷H or R⁴R⁵C═CR⁷R⁸, comprising ball-milling a phosphorus ylide ofthe formula R¹R²R³P═CR⁴R⁵ with a compound of the formula R⁷C(O)H orR⁷C(O)R⁸; wherein R¹⁻³ are independently selected from the groupconsisting of hydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl;wherein R⁴ and R⁵ are independently selected from the group consistingof hydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; andwherein R⁷ and R⁸ are independently selected from the group consistingof C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl, or aryl.

The inventive method thus produces phosphonium salts, phosphorus ylidesand olefins by means of mechanical processing of solid reagents undersolvent-free conditions. The advantages of the present invention overthe previously known, i.e. conventional solution methods, include: (1)extremely high selectivity of quaternization reactions and therefore,the relative absence of side products; (2) high yields; (3) lowprocessing temperatures; (4) simple and scalable reactions usingcommercially available equipment; and (5) the complete elimination ofsolvents from the reaction course, thus allowing for a considerablereduction in the cost of the final product and, simultaneously, for asubstantial reduction of chemical pollution caused by organic solvents.Furthermore, solvents may be needed only for separation and purificationof reaction products, which allows avoidance of environmentally harmfulliquids (e.g., toluene, benzene, hexane) and substitution withenvironmentally benign solvents such as water or supercritical CO₂.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates the preparation of phosphonium saltsaccording to the present invention.

FIG. 2 depicts the solid state ³¹P {¹H} CP MAS NMR spectra of (a)mechanochemically prepared phenacyltriphenylphosphonium bromide (Ia),(b) the conventionally synthesized salt purchased from LancasterSynthesis, and (c) (α-benzoyl-α-phenylmethylene)triphenylphosphoniumbromide (Ib) prepared mechanochemically.

FIG. 3 depicts the X-ray powder diffraction patterns, obtained using CuK_(α)-radiation, of (a) phenacyltriphenylphosphonium bromide (Ia)prepared mechanochemically by ball-milling of triphenylphosphine andα-bromoacetophenone for one hour without a solvent, and (b) commercialphenacyltriphenylphosphonium bromide (Lancaster) ball-milled for onehour under helium to achieve comparable particle size distribution andsimilar degree of crystallinity as in Ia. The SEM micrograph of theproduct Ia is shown in the inset.

FIG. 4 schematically illustrates the preparation of phosphorus ylidesaccording to the present invention, and carrying out the solvent-freeWittig-Horner reaction using such phosphorus ylides.

FIG. 5 schematically illustrates the preparation of phosphorus ylidesaccording to the present invention, and carrying out the solvent-freeWittig-Horner reaction using such phosphorus ylides.

FIG. 6 depicts the solid state ³¹P {¹H} CP MAS NMR spectra of (a)phenacyltriphenylphosphonium bromide (Ia); (b) the reaction mixtureobtained after ball-milling of phenacyltriphenylphosphonium bromide (Ia)with anhydrous K₂CO₃ for one hour; (c) the reaction mixture obtainedafter ball-milling of phenacyltriphenylphosphonium bromide (Ia) withanhydrous K₂CO₃ for three hours; (d) the commercialbenzoylmethylenetriphenylphosphorane; (e)(α-benzoyl-α-phenylmethylene)triphenylphosphorane (IVb) preparedmechanochemically; (f) the reaction mixture obtained after ball-millingtriphenylphosphine, 2-(bromometyhl)naphthalene and p-bromobenzaldehydein the presence of potassium carbonate.

FIG. 7 depicts the X-ray powder diffraction patterns of (a) the reactionmixture obtained after ball-milling phenacyltriphenylphosphonium bromide(Ia) with anhydrous K₂CO₃; and (b) the pure mechanically treatedphenacyltriphenylphosphonium bromide (Ia). Asterisks indicate Braggpeaks corresponding to potassium bromide.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a method of preparing a phosphonium salt of theformula [R¹R²R³P—CR⁴R⁵R⁶]X. The method comprises ball-milling aphosphine of the formula R¹R²R³P with a compound of the formulaXCR⁴R⁵R⁶; wherein R¹⁻³ are independently selected from the groupconsisting of hydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl;wherein R⁴⁻⁶ are independently selected from the group consisting ofhydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; and wherein Xis a mono- or polyvalent anion. The invention further provides a methodof preparing a phosphorus ylide of the formula R¹R²R³P═CR⁴R⁵. The methodcomprises ball-milling a phosphonium salt of the formula[R¹R²R³P—HCR⁴R⁵]X (i.e., wherein R⁶ is H) with a base; wherein R¹⁻³ areindependently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; wherein R⁴ and R⁵ areindependently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; and wherein X is a mono- orpolyvalent anion. A third aspect of the invention provides a method ofpreparing an olefin of the formula R⁴R⁵C═CR⁷H or R⁴R⁵C═CR⁷R⁸. The methodcomprises ball-milling a phosphorus ylide of the formula R¹R²R³P═CR⁴R⁵with a compound of the formula R⁷C(O)H or R⁷C(O)R⁸; wherein R¹⁻³ areindependently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; wherein R⁴ and R⁵ areindependently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; and wherein R⁷ and R⁸ areindependently selected from the group consisting of C₁₋₂₅ alkyl, C₃₋₈cycloalkyl, aralkyl, or aryl. Preferably, all of the above describedmethods and reactions take place in one reaction vessel (i.e., a “onepot” reaction).

The phosphonium salt, of the formula [R¹R²R³P—CR⁴R⁵R⁶]X, is formed byball-milling a phosphine of the formula R¹R²R³P with a compound of theformula XCR⁴R⁵R⁶. The substituents R¹⁻³ are independently selected fromthe group consisting of hydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl,and aryl; R⁴⁻⁶ are independently selected from the group consisting ofhydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; and X is amono- or polyvalent anion.

For purposes of the present inventive methods, X can be any mono- (−1)or polyvalent (−2, −3, etc.) anion that forms a phosphonium salt.Representative examples of X include halides (F⁻, Cl⁻, Br⁻, I⁻), sulfate(SO₄ ⁻²), sulfite (SO₃ ⁻²), nitrate (NO₃ ⁻¹phosphate (PO₄ ⁻³), andcarbonate (CO₃ ⁻²). Preferably, X is a halide; more preferably X is Cl⁻,Br⁻, or I⁻, and most preferably X is Bra⁻.

The phosphonium salt produced by the present inventive method can bephenacyltriphenylphosphonium bromide,(α-benzoyl-α-phenylmethylene)-triphenylphosphonium bromide,propane-1,3-diyl-bis(triphenylphosphonium) dibromide, or(2-naphthalenylmethyl)triphenylphosphonium bromide, and the like.

In general, the phosphorus ylide, of the formula R¹R²R³P═CR⁴R⁵, isformed by ball-milling a phosphonium salt of the formula[R¹R²R³P—HCR⁴R⁵]X in the presence of a base. The substituents R¹⁻³ areindependently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; R⁴ and R⁵ are independentlyselected from the group consisting of hydrogen, C₁₋₂₅ alkyl, C₃₋₈cycloalkyl, aralkyl, and aryl; and X is a mono- or polyvalent anion, asdescribed above. The ylide produced by the inventive method can be oneof the major types of phosphorus ylides: stabilized, semistabilized, ornonstabilized. Typically stabilized ylides can be isolated and storeduntil use, whereas semistabilized and nonstabilized are preferablyreacted with carbonyl compound in the Wittig-Homer reaction. The ylideproduced can be benzoylmethylenetriphenylphosphorane,(α-benzoyl-α-phenylmethylene)triphenylphosphorane, or(carbethoxymethylene)-triphenylphosphorane, and the like.

The base used for the transformation of the phosphonium salt into thephosphorus ylide can be of any suitable strength. The amount andstrength of the base will depend on the individual reactants, as isknown. Typical bases include alkali metal carbonate (M₂CO₃), alkalimetal hydroxides (MOH), alkali metal hydrides (ML), alkali metalalkoxides (M(OR), where R is C₁₋₆ alkyl), alkali metal amides (M(NR₂),where R is hydrogen, C₁₋₆ alkyl or aryl), or any combination thereof.The alkali metal M preferably is Li, Na, K, Rb or Cs. A preferred basefor use in the inventive method of preparing a phosphorous ylide isK₂CO₃.

In the present inventive method of preparing a phosphorous ylide, thephosphonium salt of formula [R¹R²R³P—HCR⁴R⁵]X can be formed using amethod comprising ball-milling a phosphine of the formula R¹R²R³P with acompound of the formula HCR⁴R⁵X; wherein R¹⁻³ are independently selectedfrom the group consisting of hydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl,aralkyl, and aryl; wherein R⁴ and R⁵ are independently selected from thegroup consisting of hydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl, andaryl; and wherein X is a mono- or polyvalent anion.

In the Wittig-Horner reaction, aldehydes and/or ketones are added tophosphorus ylides in order to produce olefinic products (FIG. 4). In thepresent invention, suitable aldehydes are of the formula: R⁷C(O)H, andketones are of the formula: R⁷C(O)R⁸. R⁷ and R⁸ are independently C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, or aryl. Preferably, the aldehyde orketone is used in solid form.

The present invention provides a method of preparing an olefin compoundof the formula R⁴R⁵C═CR⁷H or R⁴R⁵C═CR⁷R⁸. The method comprisesball-milling a phosphorus ylide of the formula R¹R²R³P═CR⁴R⁵ with acompound of the formula R⁷C(O)H or R⁷C(O)R⁸; wherein R¹⁻³ areindependently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; wherein R⁴ and R⁵ areindependently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; and wherein R⁷ and R⁸ areindependently selected from the group consisting of C₁₋₂₅ alkyl, C₃₋₈cycloalkyl, aralkyl, and aryl.

In the present inventive method of preparing an olefin compound, thephosphorous ylide of the formula R¹R²R³P═CR⁴R⁵ can be formed using amethod comprising comprising ball-milling a phosphonium salt of theformula [R¹R²R³P—HCR⁴R⁵]X in the presence of a base; wherein R¹⁻³ areindependently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; wherein R⁴ and R⁵ areindependently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; and wherein X is a mono- orpolyvalent anion. The phosphonium salt of the formula [R¹R²R³P—HCR⁴R⁵]Xcan be formed using the method comprising ball-milling a phosphine ofthe formula R¹R²R³P with a compound of the formula HCR⁴R⁵X; wherein R¹⁻³are independently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; wherein R⁴ and R⁵ areindependently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; and wherein X is a mono- orpolyvalent anion.

In this regard, the present invention provides a method of preparing anolefin compound of the formula R⁴R⁵C═CR⁷H or R⁴R⁵C═CR⁷R⁸. The methodcomprises: (a) ball-milling a phosphine of the formula R¹R²R³P with acompound of the formula HCR⁴R⁵X; wherein R¹⁻³ are independently selectedfrom the group consisting of hydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl,aralkyl, and aryl; wherein R⁴ and R⁵ are independently selected from thegroup consisting of hydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl, andaryl; and wherein X is a mono- or polyvalent anion to provide aphosphonium salt reaction product of the formula [R¹R²R³P—HCR⁴R⁵]X; (b)ball-milling the phosphonium salt reaction product in the presence of abase to provide a phosphorus ylide reaction product of the formulaR¹R²R³P═CR⁴R⁵, wherein R¹, R², R³, R⁴, and R⁵ are as described above;(c) ball-milling the phosphorus ylide reaction product with a compoundof the formula R⁷C(O)H or R⁷C(O)R⁸; wherein R⁷ and R⁸ are independentlyselected from the group consisting of C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl,aralkyl, and aryl, to provide an olefin reaction product; and (d)isolating the olefin reaction product. This method of preparing anolefin can further comprise the step of isolating the phosphonium saltafter step (a).

According to the methods of the present invention, the solid reactioncomponents are subjected to a mechanical processing in the absence of asolvent at about −200° C. to about 100° C., preferably at about −100° C.to about 100° C., preferably from about −10° C. to about 75° C.,preferably from about 0C to about 50° C., preferably from about 20° C.to about 40° C., and most preferably at ambient temperature (i.e., roomtemperature, about 25° C.). Preferably, the reaction takes place in achemically inert atmosphere, preferably in an inert gas atmosphere(e.g., helium, neon, argon, nitrogen, and the like).

The reaction time depends on the nature of the reactants and can vary,in general, between about 0.01 hours to about 100 hours. Preferably, thereaction time is less than 100 h, more preferably the reaction time isless than 80 h, even more preferably the reaction time is less than 60h, still even more preferably the reaction time is less than 40 h,further, more preferably the reaction time is less than 20 h, and evenmore preferably the reaction time is less than 10 h, less than 5 h, andeven less than 2 h.

The mechanical processing can be carried out in any suitable apparatus,which delivers mechanical energy into the compounds located inside theapparatus, such as, for example, a shaker-type ball-mill, a planetarymill or an attritor mill. The milling equipment can be manufactured fromtypical materials such as metal, ceramics, minerals or glass. Specificexamples of the milling equipment materials include steel and tungstencarbide. As used herein, the term “ball-milling” refers to processingusing any such suitable apparatus for carrying out the desiredmechanical processing.

After the mechanochemical processing is completed, the solvent-freesynthesis products can be further processed as desired. Any purificationscheme may be used if desired. As an illustrative example, followingisolation, additional purification may be carried out byrecrystallization from a suitable solvent, e.g., water, methanol or amethanol-hexane mixture.

While not wishing to be bound by any particular theory, several modelsdescribing mechanically induced reactions between phosphine and organichalides can be suggested. One probable mechanism when low-meltinghalides react with a phosphine (e.g., triphenylphosphine) is a localformation of low-melting eutectics in the phosphine—organic halidesystems during ball-milling. In this instance, the reactions may occurin the melt, which forms locally and momentarily in the areas where therapidly moving balls collide with both the walls of the reaction vesseland with one other. Alternatively, the reactions could occur as asequence of solid-state processes, which include: (i) breaking thecrystal lattice of a phosphonium compound and the formation of anamorphous phase; (ii) a deprotonation of an amorphous phosphonium saltby microcrystalline base (e.g., K₂CO₃) in a heterogeneous solid-statereaction.

Referring now to general terminology, as utilized generally herein, theterm “alkyl” means a straight-chain or branched alkyl substituentcontaining from, for example, about 1 to about 25 carbon atoms,preferably from about 1 to about 12 carbon atoms, preferably from about1 to about 8 carbon atoms, more preferably from about 1 to about 6carbon atoms. Examples of such substituents include methyl, ethyl,propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,iso-amyl, hexyl, octyl, dodecanyl, and the like.

The term “cycloalkyl” refers to any substituted or unsubstitutedcyclized hydrocarbon that is not considered aromatic. Preferably, thecycloalkyl contains about 3 to 8 carbons, preferably about 5 to 7carbons, more preferably about 5 to 6 carbons, and most preferably about6 carbons. The term cycloalkyl encompasses ring structures that are bothsaturated and unsaturated (i.e., single and/or double bonds). Specificexamples of cycloalkyls include, for example, cyclopropyl,cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, methcyclohexenyl, cycloheptyl, cycloheptenyl,cyclooctyl, and cyclooctenyl.

The term “aryl” refers to an unsubstituted or substituted aromaticcarbocyclic substituent (i.e., those compounds that have 4n+2 pielectrons), as commonly understood in the art, and includes monocyclicand polycyclic aromatics such as, for example, phenyl and naphthylsubstituents, and the like.

The term “aralkyl”, as utilized herein, means alkyl as defined herein,wherein at least one hydrogen atom is replaced with an aryl substituentas defined herein. Aralkyls include, for example, benzyl, phenethyl, orsubstituents of the formula:

The following examples further illustrate the invention but, of course,should not be construed as in any way limiting its scope.

EXAMPLES

The reactants and reference compounds: triphenylphosphine,α-bromoacetophenone, 2-(bromomethyl)naphthalene,(benzyl)triphenylphosphonium chloride, (methyl)triphenylphosphoniumbromide, (ethyl)triphenylphosphonium bromide,(2-naphthalenylmethyl)triphenylphosphonium bromide and2-bromo-2-phenylacetophenone and aromatic aldehydes were purchased fromAldrich or otherwise specified. Other reactants and reference compounds:anhydrous K₂CO₃, phenacyltriphenylphosphonium bromide,3-bromopropyl(triphenylphosphonium) bromide andpropane-1,3-diyl-bis(triphenylphosphonium) dibromide were purchased fromLancaster Synthesis or otherwise specified. Solid state ⁻P{¹H} CP MASNMR spectra were recorded at room temperature on a Chemagnetics Infinityspectrometer operating at 400 MHz for ¹H and equipped with a doubleresonance Chemagnetics MAS probe. A variable amplitude approach to theCP MAS method was used (contact time=0.5 ms, relaxation delay=5 s,spinning rate=20 kHz). Liquid state ¹H, ¹³C, and ³¹P NMR spectra wereobtained in CDCl₃ or C₆D₆ purchased from Cambridge Isotope Laboratories,Inc. using Varian VXR-300 and Varian VXR-400 spectrometers. Chemicalshifts are reported with respect to H₃PO₄ in water (85% solution) (³¹P)or to tetramethylsilane (¹H and ¹³C) as the external standards. TheX-ray powder diffraction experiments were performed on a Scintagdiffractometer using Cu K_(α) radiation.

Ball-milling (usually about 1.0 g total material) was performed in aSpex 8000 mill using 21 g of steel balls in a hardened-steel vial, or 70g of tungsten carbide balls in a tungsten carbide vial (when higherinput of mechanical energy was desired) sealed under helium. Forced-aircooling of the vials was employed to prevent their heating during theball-milling experiments. No heating of the milling equipment wasdetected during mechanical treatment.

Example 1

This example describes the preparation of phenacyltriphenylphosphoniumbromide (Ia), FIG. 1.

Ia was prepared from 0.70 g (2.7 mmol) of triphenylphosphine and 0.53 g(2.7 mmol) of α-bromoacetophenone by ball-milling for one hour underhelium. The resulting powder was analyzed by solid state ³¹P{¹H} CP MASNMR spectroscopy, and the salt Ia was re-crystallized from water for anadditional purification. Yield: 1.10 g (90%).

Mechanochemically prepared phenacyltriphenylphosphonium bromide (Ia):solid state ³¹P{¹H} CP MAS NMR: δ³¹P (ppm): 23.0; liquid state NMR(CDCl₃): δ³¹P (ppm): 23.0; δ¹H/J_(P-H) (ppm/Hz): 8.38/7.4 (d, 2H, Ph),8.01-7.90 (m, 6H, Ph), 7.67-7.74 (m, 4H, Ph), 7.67-7.54 (m, 6H, Ph),7.52-7.45 (m, 2H, Ph), 6.40/12.2 (d, 2H, CH₂); 270-273° C.

Phenacyltriphenylphosphonium bromide (compound Ia in FIG. 1) was alsopurchased and used as a reference. Commercialphenacyltriphenylphosphonium bromide (Lancaster Synthesis): solid state³¹P{¹H} CP MAS NMR: δ³¹P (ppm): 23.0; liquid state NMR (CDCl₃): δ³¹P(ppm): 23.0; δ¹H/J_(P-H) (ppm/Hz): 8.38/7.4 (d, 2H, Ph), 8.01-7.90 (m,6H, Ph), 7.67-7.75 (m, 4H, Ph), 7.67-7.55 (m, 6H, Ph), 7.52-7.45 (m, 2H,Ph), 6.40/12.2 (d, 2H, CH₂); Mp 268-270° C.

The solid state ³¹P{¹H} CP MAS NMR spectra of both the powder obtainedduring mechanical processing and the commercial phosphonium salt areshown in FIGS. 2a and 2 b, respectively. Both contain only one signal atthe chemical shift δ³¹P=23 ppm indicating a complete transformation oftriphenylphosphine and α-bromoacetophenone intophenacyltriphenylphosphonium bromide. In addition, the X-ray powderdiffraction pattern of the compound prepared mechanochemically in asolid state was compared with that of the commercial (i.e.,conventionally prepared in a solution) phosphonium salt that wasball-milled for one hour under helium to achieve similar particle size,concentration of defects and level of strain in both products (FIGS. 3aand 3 b). The ³¹P{¹H} CP MAS NMR spectra and the X-ray diffractionpatterns of both solids are in an excellent agreement. The SEMmicrograph of the powder obtained after ball-milling oftriphenylphosphine and α-bromoacetophenone is shown in the inset of FIG.3.

Example 2

This example illustrates the synthesis of(α-benzoyl-α-phenylmethylene)triphenylphosphonium bromide (Ib), FIG. 1.It was reported previously that 2-bromo-2-phenylacetophenone reacts withtriphenylphosphine in a solution following both path 1 and 2 shown inFIG. 1, thus yielding a mixture of C- and O-phosphorylated reactionproducts (Borowitz et al., J. Org. Chem. 34, 1595 (1969)). As a result,(α-benzoyl-α-phenylmethylene)triphenylphosphonium bromide (compound Ibin FIG. 1) is difficult to separate from by-products. The correspondingylide ((α-benzoyl-α-phenylmethylene)triphenylphosphorane) is, therefore,usually prepared in a lengthy multiple step process which avoids the useof (α-benzoyl-α-phenylmethylene)triphenylphosphonium salts (Sanz, J.Carbohydr. Chem. 17, 1331 (1998)).

The salt Ib was prepared from 0.42 g (1.6 mmol) of triphenylphosphineand 0.44 g (1.6 mmol) 2-bromo-2-phenylacetophenone by ball-milling forone hour under helium. The sample for the liquid state NMRinvestigations and the elemental analysis was re-crystallized from amethanol-diethyl ether solution for an additional purification and driedunder vacuum. Yield: 0.61 g (99%).

The solid state ³¹P NMR spectrum of the ball-milled sample contains onlyone peak centered at δ³¹P=26 ppm, consistent with the position of thesignal in the NMR spectrum of pure(α-benzoyl-α-phenylmethylene)triphenylphosphonium bromide (FIG. 2c). Thelatter was obtained in a crystalline form by re-crystallization of themechanochemically prepared sample from a methanol-diethyl ether solutionand characterized by ¹H, ³¹P, and ¹³C NMR spectroscopy in a CDCl₃solution, and elemental analysis.

Mechanochemically prepared (α-benzoyl-α-phenylmethylene)triphenylphosphonium bromide (Ib): solid state ³¹P{¹H} CP MAS NMR: δ³¹P(ppm): 26.0; liquid state NMR (CDCl₃): δ³¹P (ppm): 27.4; δ¹H/J_(P-H)(ppm/Hz): 9.30/12.4 (d, 1H, CH), 8.42 (m, 2H, Ph), 8.02-7.96 (m, 6H,Ph), 7.71-7.67 (m, 3H, Ph), 7.60-7.55 (m, 6H, Ph), 7.46-7.35 (m, 5H,Ph), 7.22-7.19 (m, 1H, Ph), 7.15-7.11 (m, 2H, Ph); δ¹³C{¹H}/J_(C-P)(ppm/Hz): 195.36/3.6 (d, CO), 135.57/9.7 (d, Ph), 134.41 (m, Ph),133.78/5.2 (d, Ph), 131.89/5.2 (d, Ph), 131.19 (s, Ph), 129. 75/13.2 (d,Ph), 129.51/2 (d, Ph), 129.17/2 (d, Ph), 128.86 (s, Ph), 128.83/5.9 (d,Ph), 118.78/86.6 Hz (d, CP, Ph), 54.30/54.9 (d, CP).

Found (%): C 70.74%, H 5.19. Calculated for C₃₂H₂₆OPBr (%): C 71.50, H4.84%; Mp 246-248° C. (decomposition).

Example 3

This example describes the preparation ofpropane-1,3-diyl-bis(triphenylphosphonium) dibromide (II), FIG. 1.

0.83 g (3.2 mmol) of triphenylphosphine and 0.50 g (1 mmol) of3-bromopropyl(triphenylphosphonium) bromide were ball-milled in atungsten carbide vial using 70 g of tungsten carbide balls for 12.5hours. The resulting powder was analyzed by the solid state NMRspectroscopy, which confirmed the formation of the salt II, then treatedwith 100 ml of chloroform, filtered, and the solvent was removed undervacuum. The compound II was isolated in 51% yield (0.40 g) andadditionally purified by re-crystallization from a methanol-hexanemixture.

Mechanochemically prepared propane-1,3-diyl-bis(triphenylphosphonium)dibromide (II): liquid state NMR (CDCl₃): δ³¹P (ppm): 25.4; δ¹H (ppm):7.87-7.83 (m, 10H, Ph), 7.71-7.57 (m, 20H, Ph), 4.64-4.55 (m, 4H, CH₂),2.3-1.83 (m, 2H, CH₂). Mp 355-360° C. (decomposition).

Commercial propane-1,3-diyl-bis(triphenylphosphonium) dibromide(Lancaster Synthesis) was compared to the mechanochemically-preparedsample. Liquid state NMR (CDCl₃): δ³¹P (ppm): 25.4; δ¹H/J_(P-H) (ppm):7.90-7.83 (m, 10H, Ph), 7.70-7.55 (m, 20H, Ph), 4.64-4.55 (m, 4H,CH₂),2.3-1.84 (m, 2H, CH₂). Mp>300° C. (decomposition).

Example 4

This example illustrates the preparation of(2-naphthalenylmethyl)-triphenylphosphonium bromide (III), FIG. 1.

0.40 g (1.5 mmol) of triphenylphosphine and 0.34 g (1.5 mmol) of2-(bromomethyl)naphthalene were ball-milled for 1 hour under helium. Theresulting powder was analyzed by the solid state ³¹P{¹H} CP MAS NMRspectroscopy, which confirmed the formation of III, and the compound IIIwas re-crystallized from methanol for an additional purification. Yield:0.70 g (95%).

Mechanochemically prepared (2-naphthalenylmethyl)triphenylphosphoniumbromide (III): liquid state NMR (CDCl₃): δ³¹P (ppm): 24.4; δ¹H/J_(P-H)(ppm): 7.98-7.1 (m, 22H, Aryl), 5.6/12.4 (d, 2H, CH₂). Mp 239-241° C.

Commercial (2-naphthalenylmethyl)triphenylphosphonium bromide (Aldrich)was compared to the mechanochemically-prepared sample: NMR (CDCl₃): δ³¹P(ppm): 24.7; δ¹H/J_(P-H) (ppm): 8.0-7.1 (m, 22H, Aryl), 5.6/12.4 (d, 2H,CH₂). Mp 237-240° C.

Example 5

This example illustrates the preparation ofbenzoylmethylenetriphenylphosphorane (IVa), FIG. 4.

Method A 0.70 g (2.7 mmol) of triphenylphosphine and 0.53 g (2.7 mmol)of α-bromoacetophenone were ball-milled for one hour, then the vial wasopened in a glove box under helium and 0.53 g (3.84 mmol) of K₂CO₃ wereadded to the reaction mixture. The vial was resealed and ball-millingcontinued for an additional three hours. The ylide IVa was isolated in99% yield (0.65 g) by dissolution of the reaction mixture in toluene,filtration, and evaporation of the solvent.

Method B 0.70 g (1.5 mmol) of phenacyltriphenylphosphonium bromide and0.25 g (1.8 mmol) of anhydrous K₂CO₃ were ball-milled for three hours.The resulting powder was analyzed by both solid state ³¹P{¹H} CP MAS NMRspectroscopy and X-ray powder diffraction, then treated with 40 ml oftoluene, filtered, and the solvent was removed by distillation undervacuum. The ylide IVa was obtained in 99% yield (0.56 g).

The spectra of the reaction mixtures formed after mechanical treatmentand that of the commercial ylide are shown in FIGS. 6b, 6 c, and 6 d,respectively. The spectrum of the sample obtained after ball-milling forone hour consists of two peaks at the chemical shift δ³¹P=23 and 17 ppm(FIG. 6b). The peak at δ³¹P=23 ppm corresponds to the startingphenacyltriphenylphosphonium bromide (FIG. 6a) remaining in the reactionmixture after one hour of ball-milling. The location of the second peakat δ³¹P=17 ppm is the same as the signal in the solid state ³¹P{¹H} CPMAS NMR spectrum of the commercial benzoylmethylenetriphenylphosphorane(FIG. 6d). After ball-milling for three hours, the solid state NMRspectrum of the reaction mixture (FIG. 6c) contains only one peak atδ³¹P=17 ppm indicating a complete transformation ofphenacyltriphenylphosphonium bromide into thebenzoylmethylenetriphenylphosphorane (IVa).

The X-ray powder diffraction analysis (FIG. 7) also confirms thecompletion of the transformation during ball-milling. The X-ray powderdiffraction pattern of the powder sample after mechanical processingcontains strong Bragg peaks of potassium bromide (KBr), which is one ofthe expected reaction products, and a set of peaks corresponding tomicro/nano-crystalline phases completely different from that of thestarting compounds.

Mechanochemically prepared benzoylmethylenetriphenylphosphorane: solidstate ³¹P{¹H} CP MAS NMR: δ³¹P (ppm): 17.0; liquid state N (CDCl₃): δ³¹P(ppm): 18.3; δ¹H/J_(P-H) (ppm/Hz): 8.38/8.1, 1.5 (dd, 2H, Ph), 7.74 (m,6H, Ph), 7.24 (m, 6H, Ph), 7.00 (m, 6H, Ph), 4.56/25.7 (d, 1H, CH); Mp178-183° C.

Commercial benzoylmethylenetriphenylphosphorane (Alfa Aesar) wascompared to the product prepared by Methods A and B: solid state ³¹P{¹H}CP MAS NMR: δ³¹P (ppm): 17.0; liquid state NMR (CDCl₃): δ³¹P (ppm):18.3; δ¹H/J_(P-H) (ppm/Hz): 8.37/8.1, 1.5 (dd, 2H, Ph), 7.77-7.70 (m,6H, Ph), 7.26-7.22 (m, 6H, Ph), 7.04-6.93 (m, 6H, Ph), 4.56/25.3 (d, 1H,CH); Mp 182-185° C.

Example 6

This example illustrates the preparation of(α-benzoyl-α-phenylmethylene)-triphenylphosphorane (IVb), FIG. 4.

0.60 g (2.29 mmol) of triphenylphosphine and 0.63 g (2.29 mmol) of2-bromo-2-phenylacetophenone were ball-milled for one hour, then thevial was opened in a glove box under helium, and 0.5 g (3.62 mmol) ofK₂CO₃ was added to the reaction mixture. The vial was resealed andball-milling continued for additional three hours. The formation of IVbwas confirmed by the solid state ³¹P NMR spectroscopy. The phosphoraneIVb was isolated by dissolution of the solid reaction mixture intoluene, filtration, and evaporation of the solvent. Yield 1.0 g (99%).

(α-benzoyl-α-phenylmethylene)triphenylphosphorane: solid state ³¹P{ ¹H}CP MAS NMR: δ³¹P (ppm): 16.0; liquid state NMR (CDCl₃): δ³¹P (ppm):16.64 {lit. (Aitken et al., Phosphorus, Sulfur and Silicon 101,281(1995))δ³¹P=16.0 ppm}; δ¹H (ppm): 7.63-7.56 (m, 6H, Ph), 7.47-7.40 (m,11H, Ph), 7.09-7.06 (m, 3H, Ph), 6.86 (s, 5H, Ph); δ¹³C{¹H}/J_(C-P)(ppm/Hz): 184.10/5.0 (d, CO), 141.35/11.5 (d, Ph), 138.91/11.5 (d, Ph),137.75/4.6 (d, Ph), 133.45/9.6 (d, Ph), 131.19/2.6 (d, Ph), 128.95 (s,Ph), 128.35/12.2 (d, Ph), 128.13 (s, Ph), 127.30/1.9 (d, Ph),127.10/90.8 (d, CP, Ph), 126.96 ppm(s, Ph), 124.65/2.7 (d, Ph),72.90/109.1 (d, CP); MS (70 eV, EI): m/z (%): 456 (100) [M⁺], 379 (15)[M⁺-C₆H₅], 262 (12) [(C₆H₅)₃P⁺], 183 (15); 178 (33), 165 (15); Mp192-194° C. {lit.: 192-194° C. (Aitken et al., Phosphorus, Sulfur andSilicon 101, 281 (1995))}.

Example 7

This example describes the preparation of(carbethoxymethylene)-triphenylphosphorane (VIa), FIG. 5.

(Carbethoxymethylene)triphenylphosphorane (VIa) was prepared from 3.0 g(6.98 mmol) of (carbethoxymethylene)triphenylphosphonium bromide (Va)and 2.0 g (14.49 mmol) of anhydrous K₂CO₃ during mechanical processingfor four hours. The completion of the reaction was confirmed by thesolid state ³¹P MAS NMR spectroscopy. After dissolving the ball-milledpowder in toluene and filtration, the ylide VIa was isolated in 96%yield (2.34 g).

(Carbethoxymethylene)triphenylphosphorane (VIa). Solid state ³¹P MASNMR: δ³¹P (ppm): 1; liquid state NMR (C₆D₆): δ³¹P (ppm): 19.3 {lit.:δ³¹P=17.9 ppm (Climent et al., J. Org. Chem. 54, 3695 (1989))};δ¹H/J_(P-H) (ppm/Hz): 7.69-7.58 (m, 6H, Ph), 7.07-6.95 (m, 9H, Ph),4.43/7 (q, 2H, CH₂), 3.34/23.8 (d, 1H, CH), 1.25/7 (t, CH₃);δ¹³C{¹H}/J_(C-P) (ppm/Hz): 172.4/14 (d, CO), 141.35/11.5 (d, Ph),138.91/11.5 (d, Ph), 133.70/9.9 (d, Ph), 132.05/2.3 (d, Ph), 129.95 (s,Ph), 129.09/11.8 (d, Ph), 58.34 (s, Et), 30.16/30.1 (d, CH), 15.96 (s,Et) {lit.: liquid state NMR (CDCl₃): δ¹H/J_(P-H) (ppm/Hz): 8.0-7.3 (m,Ph), 3.99/7 (q, CH₂), 2.91 (br, CH), 1.07/7 (t, CH₃) (Weleski et al., J.Organomet. Chem. 102, 365 (1975))}; MS (70 eV, EI) m/z (%): 347 (60)[M⁺], 319 (27) [M⁺-Et], 303 (52) [M⁺-OEt], 275 (100), 196 (12) 183 (4),165 (8); Mp 125-128° C. {lit.: m.p. 125-127.5° C. (Kolodiazhny,Phosphorus ylides, Wiley-VCH, Weincheim, 1999)}.

Example 8

This example describes the preparation of1-(p-bromophenyl)-2-(naphthyl)ethylene (VII), FIG. 4.

0.50 g (1.91 mmol) of triphenylphosphine, 0.42 g (1.90 mmol) of2-bromomethylnaphthalene, 0.36 g (1.98 mmol) of p-bromobenzaldehyde, and0.50 g (3.62 mmol) of K₂CO₃ were placed in a hardened-steel vial in aglove box under helium. The vial was sealed, and the sample wasball-milled for eight hours. The formed powder was first analyzed bysolid state ³¹P{¹H} CP MAS NMR spectroscopy, then loaded on a silica gelchromatography column, and the mixture of (E)- and(Z)-1-(p-bromophenyl)-2-(naphthyl)ethylenes (VII) (E:Z ratio ca. 3.5:1by ¹H NMR in CDCl₃) was isolated in 93% yield, (0.54 g ) by eluationwith hexane and toluene. Triphenylphosphine oxide was further obtainedfrom the same column in 92% yield (0.53 g) using a hexane-acetonemixture as an eluant. The separation and purification of the E-isomerwas performed according to the previously described procedure (Brooks etal., J. Am. Chem. Soc. 121, 5444 (1999)) by the column chromatography onsilica gel.

The solid state ³¹P{¹H} CP MAS NMR spectrum of the obtained powdercontained only one peak at δ³¹P=25 ppm (FIG. 5e), which corresponds tothe position of the signal in the solid state ³¹P NMR spectrum oftriphenylphosphine oxide (Arumugam et al, J. Chem. Soc., Chem. Comm. 724(1992)). Also, the ³¹P and ¹H NMR spectroscopy in the solution (CDCl₃)confirmed the completion of the reaction as shown in FIG. 4. The (E)-and (Z)-isomers of VII in the reaction mixture formed in a 3.5:1 ratioas determined from the ¹H NMR spectrum in CDCl₃. Thus, themechanochemical reaction is considerably more selective when comparedwith the similar process in the solution, where trans to cis ratio wasfound to be approximately 0.4:1 (Brooks et al., J. Am. Chem. Soc. 121,5444 (1999)).

(E)-1-(p-Bromophenyl)-2-(naphthyl)ethylene (VII): liquid state NMR(CDCl₃): δ³¹H/J_(H-H) (ppm/Hz): 7.85-7.77 (m, 4H, Ph), 7.72/8.8, 1.7(dd, 1H, Ph), 7.51-7.40 (m, 6H, Ph), 7.26/14, 7.16/14 (dd, 2H, CH);δ¹³C{¹H} (ppm):136.51, 134.63, 133.86, 133.34, 132.04, 129.69, 128.62,128.24, 128.20, 127.93, 127.09, 126.64, 126.29, 123.57, 121.58; MS (70eV, EI): m/z (%): 308/310 (100/88) [M⁺], 229 (51) [M⁺-HBr], 228 (91)[M⁺-2H-Br], 202 (15), 128 (10) [C₁₀H₈ ⁺], 114 (55); 101 (29); Mp186-189° C. {lit.: 188.5-189° C. (Brooks et al., J. Am. Chem. Soc. 121,5444 (1999))}.

Triphenylphosphine oxide: solid state ³¹P MAS NMR: δ³¹P (ppm): 25;liquid state NMR (CDCl3): δ³¹P (ppm): 30.2; δ¹H (ppm): 7.70-7.63 (m 6H,Ph), 7.56-7.42 (m, 12H, Ph), δ¹³C{¹H}/J_(C-P) (ppm) 133.22, 132.13,132.00, 131.93, 131.84, 128.55 128.39; Mp 155-57° C. {lit.: 152-153,157° C. (The Aldrich library of ¹³ C and ¹ H FT NMR spectra, Ed. I,Eds.: C. J. Pouchert, J. Behnke, Aldrich Chemical Company, Inc. p. 1691,1993)}.

Example 9

This example illustrates the preparation of 4-bromostilbene (VIII) insitu from (benzyl)triphenylphosphonium chloride, K₂CO₃, andp-bromobenzaldehyde, FIG. 4.

0.70 g (180 mmol) of (benzyl)triphenylphosphonium chloride, 0.33 g (1.80mmol) of p-bromobenzaldehyde and 0.50 g (3.62 mmol) of K₂CO₃ were placedinto a hardened-steel vial in a glove box under helium. The vial wassealed in helium atmosphere and the sample was ball-milled for eighthours. The formed powder was first analyzed by the solid- and liquidstate NMR spectroscopy, then loaded on a silica gel chromatographycolumn, and the mixture of (E)- and (Z)-4-bromostilbenes (VIII) wasisolated by eluation with hexane and toluene (E:Z ratio ca. 2:1 by ¹HNMR in CDCl₃) in 90% yield (0.45 g). Triphenylphosphine oxide wasfurther obtained from the same column in 90% yield (0.44 g) using ahexane-acetone mixture as an eluant.

(E)-4-Bromostilbene (VIII): liquid state NMR (CDCl₃): δ¹H/J_(H-H)(ppm/Hz): 7.5-7.44 (m, 4H, Ph), 7.37-7.33 (m, 4H, Ph), 7.28-7.21 (m, 1H,Ph) 7.08/16.3. 7.01/16.3 (dd, 2H, CH); δ¹³C{¹H} (ppm):137.11,136.44,131.95, 129.58, 128.92, 128.15, 128.08, 127.65, 126.74, 121.49;MS (70 eV, EI): m/z (%): 260/258 (99/98) [M⁺], 179 (37) [M⁺-Br], 178(100) [M⁺-HBr], 151 (10), 89 (15) 76 (7); Mp 132-135° C. {lit.: 132-133°C. (Kumari et al., J. Organometallic Chem. 96, 237 (1975); Christoforouet al., Aust. J. Chem. 35, 729-(1982))}.

Example 10

This example illustrates the preparation of1-(phenyl)-2-(naphthyl)ethylene (IXa), FIG. 5.

0.90 g (2.31 mmol) of (benzyl)triphenylphosphonium chloride (Vc), 0.36 g(2.31 mmol) of 2-naphthaldehyde and 0.60 g (4.35 mmol) of anhydrousK₂CO₃ were placed into a hardened-steel vial in a glove box underhelium. The vial was sealed in helium atmosphere and the sample wasball-milled for seven hours. The formed powder was first analyzed by thesolid state ³¹P MAS NMR spectroscopy, which revealed one signalcorresponding to triphenylphosphine oxide at δ³¹P=25 ppm. 1.7 g of thepowder was loaded on the top of a silica-gel filled chromatographiccolumn, and the mixture of (E)- and (Z)-1-(phenyl)-2-(naphthyl)ethylenes(IXa) was isolated by eluation with a hexane—toluene mixture in 85%yield, (0.41 g ). Triphenylphosphine oxide was further obtained from thesame column in 82% yield (0.48 g) using a hexane-acetone mixture as aneluant. The partial separation of the E-isomer (0.25 g) was accomplishedby the column chromatography on silica gel. Based on the amounts ofisolated products, E/Z-isomer ratio was estimated to be at least 1.6:1.

(E)-1-(phenyl)-2-(naphthyl)ethylene (IXa): Liquid state NMR (CDCl₃):δ¹H/J_(H-H) (ppm/Hz): 7.82-7.78 (m, 4H), 7.72/8.4 (d, 1H), 7.54/8.2 (d,2H), 7.74-7.37 (m, 4H), 7.28-7.18(m, 3H); δ¹³C{¹H} (ppm): 137.27,134.74, 133.63, 132.97, 128.95, 128.69, 128.65, 128.23, 127.93, 127.62,126.57, 126.48, 126.26, 125.82, 123.44 (lit. (Brooks et al., J. Am.Chem. Soc. 121, 5444 (1999)): liquid state NMR (CDCl₃): δ¹H/J_(H-H)(ppm): 7.87-7.80 (m, 4H), 7.72/8.4, 1.6 (dd, 1H), 7.54/8.2 1.0 (dd, 2H),7.45/6.7, 1.7 (td, 1H), 7.39/7.6 (t, 2H), 7.30/16 (d, 1H), 7.29/7.2, 1.6(dt, 1H,), 7.24/16.4 (d, 1H); δ¹³C{¹H} (ppm): 137.57, 135.03, 133.92,133.25, 129.24, 128.94, 128.53, 128.21, 127.90, 126.84, 126.76, 126.55,126.11, 123.71}; MS (70 eV, EI) m/z (%): 230 (100) [M⁺], 215 (5), 202(1.8), 152 (1) 114 (2); Mp 145-148° C. {lit.: 147-148° C. Brooks et al.,J. Am. Chem. Soc. 121, 5444 (1999)}.

(Z)-1-(phenyl)-2-(naphthyl)ethylene (IXa): Liquid state NMR (CDCl₃,after extraction of the signals of the E-isomer): δ¹H/J_(H-H) (ppm/Hz):7.74-7.67 (m, 2H), 7.61/8.5 (d, 1H), 7.47-7.38 (m, 2H), 7.54/8.5 1.2(dd, 1H) 7.28-7.25(m, 2H), 7.21-7.17 (m, 3H), 6.73/12.0 (d, 1H),6.65/12.4 (d, 1H); δ¹³C{¹H} (ppm): 137.03, 134.67, 133.26, 132.36,130.41, 129.98, 128.78, 128.04, 127.80, 127.55, 127.41, 126.30, 127.03,126.75, 125.81, 125.69 {lit. Brooks et al., J. Am. Chem. Soc. 121, 5444(1999): liquid state NMR (CDCl₃): δ¹H (ppm): 7.79-7.74 (m, 1H), 7.73 (s,1H), 7.64/8.5 (d, 1H), 7.45-7.38 (m, 2H), 7.35/8.8, 1.6 (dd, 1H)7.30-7.25(m, 2H), 7.24-7.18 (m, 3H), 6.76/12.0 (d, 1H), 6.68/12.4 (d,1H); δ¹³C{H₁}/J_(C-P)(ppm/Hz): 137.43, 135.07, 133.65, 132.75, 130.80,130.38, 129.18, 128.43, 128.19, 128.15, 127.81, 127.68, 127.42, 127.14,126.20, 126.08}.

Example 11

This example illustrates the preparation of 2-ethenylnaphthalene (IXb),FIG. 5.

2-ethenylnaphthalene (IXb) was prepared from 0.90 g (2.52 mmol) of(methyl)triphenylphosphonium bromide (Vb), 0.33 g (2.56 mmol) ofnaphthaldehyde and 1.06 g (7.68 mmol) of anhydrous K₂CO₃ by ball-millingfor a total of 20 hours. The mechanical processing was interrupted afterfive, ten and 16 hours and the samples for analysis where extracted fromthe vial in a glove box under helium, then the vial was resealed andball-milling continued. After 20 hours of mechanical treatment, theformed powder was analyzed by the solid- and liquid state NMRspectroscopy, then 1.76 g of the powder was loaded on the top of asilica gel chromatography column, and the compound IXb was isolated byeluation with a hexane—toluene mixture in the 73% yield, (0.21 g).Triphenylphosphine oxide was further obtained from the same column in80% yield (0.39 g) using a hexane-acetone mixture as an eluant. The ³¹PNMR spectrum of the powder after ball-milling for 20 h contained twosignals: a major signal corresponding to triphenylphosphine oxide atδ³¹P=25 ppm and a very weak signal from the starting phosphonium salt Vbat δ³¹P=21 ppm.

2-Ethenylnaphthalene (IXb): Liquid state NMR (CDCl₃): δ¹H/J_(H-H)(ppm/Hz): 7.75-7.69 (m, 4H, Ph), 7.58/8.8, 1.2 (dd, 1H, Ph), 7.43-7.37(m, 2H, Ph) 6.83/17.6, 10.9 (dd, 1H, CH), 5.83/17.6 (d, 1H, CH),5.29/10.9 (d, 1H, CH); δ¹³C{¹H} (ppm): 136.86, 134.92, 133.49, 133.08,128.08, 127.98, 127.59, 126.32, 126.14, 125.82, 123.08, 114.08 {lit.(Katritzky, et al., Magn. Reson. Chem. 29, 2 (1991)): liquid state NMR(CDCl₃): δ¹H/J_(H-H) (ppm/Hz): 7.71, 7.70, 7.65, 7.55, 7.38, 7.36,6.80/17.6, 10.9 (dd, CH), 5.80/17.6 (d, CH), 5.27/10.9 (d, CH); δ¹³C{¹H}(ppm):136.86, 134.92, 133.49, 133.09, 128.09, 127.99, 127.60, 126.35,126.15, 125.83, 123.07, 114.07};MS (70 eV, EI): m/z (%): 154 (100) [M⁺],128 (11); Mp 58-61° C. {lit.: 61-62° C. (Ando, et al., J. Organomet.Chem. 133, 219 (1977))}.

Example 12

This example illustrates the preparation of1-(4-bromophenyl)-1-methyl-2-phenylethylene (IXc), FIG. 5.

1-(4-Bromophenyl)-1-methyl-2-phenylethylene (IXc) was prepared from 0.85g (2.18 mmol) of (benzyl)triphenylphosphonium chloride (Vc), 0.44 g(2.20 mmol) of p-bromoacetophenone and 0.5 g (3.62 mmol) of anhydrousK₂CO₃ by ball-milling for 14 hours. The formed powder was analyzed bythe solid state ³¹P MAS NMR spectroscopy. The solid state ³¹P MAS NMRspectrum of the ball-milled powder contained two signals: a major signalcorresponding to triphenylphosphine oxide at δ³¹P =25 ppm and a minorsignal corresponding to the starting phosphonium salt at δ³¹P=22 ppm,the estimated ratio ˜7:1. 1.44 g of the powder was loaded on the top ofa silica-gel filled chromatographic column, and the mixture of (E)- and(Z)-isomers was isolated by eluation with a hexane—toluene mixture (E:Zratio ca. 3.4:1 by ¹H NMR in CDCl₃) in the 70% yield, (0.34 g).Triphenylphosphine oxide was further obtained from the same column in73% yield (0.36 g) using a hexane-acetone mixture as an eluant. Theattempt to separate the (E)- and (Z)-isomers was unsuccessful.Assignment of the signals in the ¹H NMR spectrum of the reactionproducts was performed according to the literature (see, e.g., Beller,et al., Eur. J. Inorg. Chem. 1998, 29).

1-(4-Bromophenyl)-1-methyl-2-phenylethylene (IXc): Liquid state NMR(CDCl₃): δ¹H/J_(H-H) (ppm/Hz): 7.45-7.43 (m, Ph), 7.36-7.32 (m, Ph),7.25-7.21 (m, Ph) 7.10-7.01 (m, Ph), 6.94-6.92 (m, Ph) 6.79 (s, CHE-isomer), 6.46 (s, CH, Z-isomer), 2.21/1.3 (d, CH₃, E-isomer), 2.1/1.4(Z-isomer); δ¹³C{¹H} (ppm):142.81, 140.92, 138.02, 137.29, 137.26,136.29, 131.69, 131.45, 130.11, 129.22, 129.20, 129.04, 128.32, 128.25,128.23, 128.09, 127.71, 127.38, 126.79, 126.44, 121.17, 120.92, 29.98,26.96, 17.57; MS (70 eV, EI): m/z (%): 272/274 (53/57) [M⁺], 191 (24)[M⁺-Br], 178 (100),165 (15), 152 (12), 115(65), 102 (22), 89 (30) 77(29).

Example 13

This example illustrates the preparation of1-(ethyl)-2-(naphthyl)ethylene (IXd), FIG. 5.

1-(ethyl)-2-(naphthyl)ethylene (IXd) was prepared from 1.00 g (2.7 mmol)of (ethyl)triphenylphosphonium bromide (Vd), 0.42 g (2.7 mmol) ofnaphthaldehyde and 0.79 g (5.5 mmol) of anhydrous K₂CO₃ by ball-millingfor 26 hours. The formed powder was analyzed by the solid state ³¹P MASNMR spectroscopy. The solid state ³¹P MAS NMR spectrum of theball-milled powder contained two signals: a major signal correspondingto triphenylphosphine oxide at δ³¹P=25 ppm and a minor signalcorresponding to the starting phosphonium salt at δ³¹P=30 ppm, theestimated ratio ˜8:1. The powder (2.0 g) was loaded on the top of asilica-gel filled chromatographic column, and the mixture of (E)- and(Z)-isomers was isolated by eluation with a hexane-toluene mixture (E:Zratio ca. 1:1 by ¹H NMR in CDCl₃) in the 63% yield, (0.26 g).Triphenylphosphine oxide was further obtained from the same column in80% yield (0.61 g) using a hexane-acetone mixture as an eluant.Assignment of the signals in the ¹³C and ¹H NMR spectra of the reactionproducts was performed according to the literature (see, e.g.,Kulasegarm, et al., J. Org. Chem. 62, 6547 (1997); Kulasegarm et al.,Tetrahedron 54, 1361(1998)).

1-(ethyl)-2-(naphthyl)ethylene (IXd): Liquid state NMR (CDCl₃):δ¹/J_(H-H) (ppm/Hz): 7.83-7.45 (m, Ph), 7.66 (s, Ph), 7.58-7.55 (m, Ph),7.48-7.40, 6.63-6.54 (m, CH E- and Z-isomer), 6.40-6.31 (m, CH,E-isomer), 5.90-5.86 (m, E-isomer), 2.01/7.3, 1.4 (dd), 1.94/6.4, 1.3(dd) (CH₃, E- and Z-isomer); δ¹³C{I¹H} (ppm): 135.53, 135.30, 133.89,133.53, 132.79, 132.29, 131.34, 130.08, 128.20, 128.08, 128.07, 127.99,127.77, 127.74, 127.73, 127.66, 127.47, 127.36, 126.24, 125.15, 125.78,125.55, 125.37, 123.66, 18.8, 14.97 MS (70 eV, EI): m/z (%): 168 (100)[M⁺], 153 (28) [M⁺-CH₃], 141 (10), 115(9)

Example 14

This example illustrates the preparation of 4-bromostyrene (IXe), FIG.5.

4-bromostyrene (IXe) was prepared from 1.15 g (3.22 mmol) of(methyl)triphenylphosphonium bromide (Vb), 0.60 g (3.24 mmol) ofp-bromoacetophenone and 1.50 g (10.8 mmol) of anhydrous K₂CO₃ byball-milling for 22.5 hours. The formed powder was analyzed by the solidstate ³¹P MAS NMR spectroscopy. The solid state ³¹P MAS NMR spectrum ofthe ball-milled powder contained the signal at δ³¹P=25 ppm correspondingto triphenylphosphine oxide. The powder (2.5 g) was used for theseparation of 4-bromostyrene (IXe) by distillation in vacuum. B. p. 38°C. at 0.1 mm of Hg. The yield 60% (0.34 g). Assignment of the signals inthe ¹³C and ¹H NMR spectra of Xe was performed according to theliterature (see, e.g., Happer et al., J. Chem. Soc. Perkin Trans. II1984, 1673; Echavarren et al., J. Am. Chem. Soc. 109,5485 (1987)).

4-bromostyrene (IXe): Liquid state NMR (CDCl₃): δ¹H/J_(H-H) (ppm/Hz):7.43-7.41 (m, Ph), 7.24-7.23 (m, Ph), 6.62/17.4, 10.9 (dd, CH),5.72/17.5 (d, CH₂), 5.25/10.9 (d, CH₂); δ¹³C{¹H} (ppm):136.28, 135.55,131.45, 127.60,121.45, 114.45

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

What is claimed is:
 1. A method of preparing a phosphonium salt of theformula [R¹R²R³P—CR⁴R⁵R⁶]X, which method comprises ball-milling aphosphine of the formula R¹R²R³P with a compound of the formulaXCR⁴R⁵R⁶; wherein R¹⁻³ are independently selected from the groupconsisting of hydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl;wherein R⁴⁻⁶ are independently selected from the group consisting ofhydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; wherein X isa mono- or polyvalent anion; and wherein the method optionally takesplace in one reaction vessel.
 2. The method of claim 1, wherein thephosphonium salt is selected from the group consisting ofpropane-1,3-diyl-bis(triphenylphosphonium) dibromide—, and(2-naphthalenylmethyl)triphenylphosphonium bromide.
 3. A method ofpreparing a phosphorus ylide of the formula R¹R²R³P═CR⁴R⁵, which methodcomprises ball-milling a phosphonium salt of the formula[R¹R²R³P—HCR⁴R⁵]X in the presence of a base; wherein R¹⁻³ areindependently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; wherein R⁴ and R⁵ areindependently selected from the group consisting of hydrogen, C₁₋₂₅alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; wherein X is a mono- orpolyvalent anion; and wherein the method optionally takes place in onereaction vessel.
 4. The method of claim 3, wherein the base is K₂CO₃. 5.The method of claim 3, wherein the phosphonium salt of the formula[R¹R²R³P—HCR⁴R⁵]X, is formed using a method comprising ball-milling aphosphine of the formula R¹R²R³P with a compound of the formula HCR⁴R⁵X;wherein R¹⁻³ are independently selected from the group consisting ofhydrogen, C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; wherein R⁴and R⁵ are independently selected from the group consisting of hydrogen,C₁₋₂₅ alkyl, C₃₋₈ cycloalkyl, aralkyl, and aryl; and wherein X is amono- or polyvalent anion.
 6. A method of preparing a phosphonium saltselected from the group consisting of phenacyltriphenylphosphoniumbromide and (α-benzoyl-α-phenylmethylene)-triphenylphosphonium bromide,which method comprises ball-milling triphenylphosphine with phenacylbromide or α-benzoyl-α-phenylmethylene bromide to produce thecorresponding phosphonium salt; and wherein the method optionally takesplace in one reaction vessel.
 7. The method of claim 6, wherein thephosphonium salt is phenacyltriphenylphosphonium bromide.
 8. The methodof claim 6, wherein the phosphonium salt is(α-benzoyl-α-phenylmethylene)-triphenylphosphonium bromide.
 9. A methodof preparing a phosphorus ylide selected from the group consisting ofbenzoylmethylenetriphenylphosphorane,(α-benzoyl-α-phenylmethylene)triphenylphosphorane, and(carbethoxymethylene)-triphenylphosphorane, which method comprisesball-milling a corresponding phosphonium salt in the presence of a base;and wherein the method optionally takes place in one reaction vessel.10. The method of claim 9, wherein the phosphorus ylide isbenzoylmethylenetriphenylphosphorane.
 11. The method of claim 9, whereinthe phosphorus ylide is(α-benzoyl-α-phenylmethylene)triphenylphosphorane.
 12. The method ofclaim 9, wherein the phosphorus ylide is(carbethoxymethylene)-triphenylphosphorane.